There is an extreme need to develop safer and more efficacious modes of prophylactic and therapeutic vaccination. This need is particularly acute in the area of non-conventional pathogens, such as anthrax and smallpox, due to the ease of weaponizing these agents, and the inadequacy of current prevention and treatment regimens. The goal of this multi-project program proposal is to develop novel, first-in-class immune activating agents to be used as enhanced adjuvants for nonconventional pathogens. Specifically, we aim to exploit the unique power of the chemokine system (a primary regulator of the trafficking patterns of the body's immune cells) to target both the innate immune response and acquired immunity. This will be done by exploiting chemokine-based modalities recently characterized in our organization. Specifically, the following approaches will be employed: (i) The use of a newly discovered chemokine-derived peptide, designated SHAAGtide (or PDX-S), identified here as a high affinity ligand for the formyl peptide receptor-related molecule FPRL-1, to actively engage innate immune responses; (ii) Using a virally derived chemokine vMCK-2 (or PDX-K), a highly potent attractant of APC and DC in vivo, to enhance acquired immune responses; (iii) The creation of novel medicinal chemical ligands ('chemomimetics') for FPRL-1 and the PDX-K receptor to provide new adjuvant modalities with an expanded range of administration routes; (iv) The creation of in vivo targeting and vaccine delivery vehicles, and finally, (v) Comparative assessment of all such modalities in mouse and non-human primate models to determine which agent (PDX-S, PDX-K, chemomimetic, etc) and form (soluble protein, DNA, medicinal chemical, or viral) shall be advanced through preclinical and into clinical development. Thus we aim to create powerful 'superadjuvants' - with markedly enhanced qualities over currently used adjuvants -for use in protection against Category A-C pathogens.